ORGANIC LETTERS
Regioselective Synthesis of Unsymmetrical 3,5-Dialkyl-1-arylpyrazoles
2000 Vol. 2, No. 20 3107-3109
Xiao-jun Wang,* Jonathan Tan, and Li Zhang Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877
[email protected] Received July 11, 2000
ABSTRACT
3-Alkoxylmethyl-5-alkylpyrazoles undergo regioselective N-arylation with 4-fluoronitrobenzene in the presence of base to yield the corresponding 1-(4-nitro-phenyl)pyrazoles. Further elaboration of these intermediates furnishes a practical synthesis of unsymmetrical 3,5-dialkyl-1-arypyrazoles. A tentative explanation of the observed regioselectivities is provided.
In connection with a recent medicinal chemistry program, we required a practical synthesis of unsymmetrical 3,5dialkyl-1-arylpyrazoles. We were particularly interested in the large-scale synthesis of 3-isopropyl-5-ethylpyrazole 1 and 3-methyl-5-ethylpyrazole 2. Aromatic substitution of N-
on arylation of pyrazole 3 with 4-fluoronitrobenzene 4 (Scheme 1). We anticipated that the isopropyl and ethyl
Scheme 1
nonsubstituted pyrazoles with activated halogenated benzenes such as 4-fluoronitrobenzene has been a powerful method for synthesis of N-arylpyrazoles.1 However, the reaction generally gives a mixture of two regioisomers since pyrazole is an ambident nucleophile. In an effort to directly introduce the 4-nitrophenyl on pyrazole nitrogen, we initially focused (1) (a) Kost, A. N.; Grandberg, I. I. In Progress in Pyrazole Chemistry; Kartrizky, A. R., Boulton, A. J., Eds.; AdVances in Heterocyclic Chemistry; Academic Press: New York, 1966; Vol. 6, p 347. (b) Elguero, J. In Pyrazoles and their Benzo DeriVatiVes; Katrizky, A. R., Rees, C. W., Eds.; ComprehensiVe Heterocyclic Chemistry; Pergamon Press: Oxford, 1984; Vol. 5, p 167. 10.1021/ol0001822 CCC: $19.00 Published on Web 09/02/2000
© 2000 American Chemical Society
groups in pyrazole 3 would have different steric requirements2 and arylation would favor the regioisomer 3a which would be subsequently transformed to pyrazole 1. Surpris(2) Wang, X.-j.; Tan, J.; Grozinger, K.; Betageri, R.; Kirrane, T.; Proudfoot, J. R. Tetrahedron Lett. 2000, 41, 5321.
ingly, arylation of pyrazole 3 using t-BuOK as base in DMSO at 70 °C afforded a 1.2:1 mixture of pyrazoles 3a and 3b.3 Although a careful chromatographic purification separated the two isomers, it was clearly an impractical approach to the pyrazole 1, which we needed in a large quantity. By extension, one can suppose that this approach would not furnish a practical synthesis of pyrazole 2. As shown in Scheme 2, we envisioned that the presence of an appropriately positioned chelating group such as I
Scheme 2
7:1 mixture of 5a and 5b, in agreement with a chelation effect. The same reaction was conducted in THF using t-BuOLi, NaH, and EtMgBr as bases, respectively, and a very similar ratio of 5a and 5b was obtained in each case. These bases showed sluggish reactions with less conversion compared with the potassium salt. Arylation of pyrazole 6 in THF yielded products 6a and 6b in a ratio of 16:1, suggesting that a stronger chelation effect by the branched ether side chain led to a significant improvement of regioselectivity, in agreement with the Thorpe-Ingold effect. Here as well, DMSO as solvent gave a 2:1 mixture of isomers 6a and 6b. With pyrazoles 7 and 8, both bearing a larger R2 group (i-Pr), arylation yielded regioisomers 7a and 7b as a 4:1 mixture and 8a and 8b as a 11:1 mixture in THF, respectively, in contrast to 1:1 mixtures in DMSO. The regioselectivity for the latest two cases is slightly lower than those of 5 and 6, probably due to the presence of the more steric demanding i-Pr group. Using the newly devised approach to control regioselectivity, a practical synthesis of pyrazole 1 was achieved as outlined in Scheme 4. The THP groups of the mixture of 6a
Scheme 4
might block access of the electrophile and favor arylation on the pyrazole anion II, leading regioselectively to Narylpyrazole IV.4 The alkoxy group of IV could be further converted to the isopropyl group in 1 and methyl group in 2 later in the synthesis. We began this study with pyrazole 5, and the related results are summarized in Scheme 3.
Scheme 3
Arylation was first carried out with 4-fluoronitrobenzene using t-BuOK as base in DMSO at 70 °C for 1 h, and a 1:1 mixture of regioisomers 5a and 5b was obtained. When THF was used as solvent instead of DMSO, arylation produced a (3) Malhotra, N.; Falt-Hansen, B.; Becher, J. J. Heterocycl. Chem. 1991, 28, 1837. 3108
and 6b were deprotected with p-TsOH in aqueous methanol, and major isomer 9a was isolated in 62% yield over three steps5 simply by crystallization of the crude material in a 4:1 mixture of hexane and ethyl acetate. MnO2 oxidation of 9a followed by the Wittig reaction of the resulting ketone 10 gave vinyl compound 11 in 60% yield. Reduction of the double bond and nitro group in 11 was conducted in one pot with 10% Pd/C under H2, yielding pyrazole 1. As for the scale-up of pyrazole 2, the crude mixture of 5a and 5b (7:1) was similarly treated with p-TsOH in aqueous methanol. The resulting major isomer 12a, free of its regioisomer 12b, was isolated in 45% yield over three steps5 by recrystallization from 4:1 mixture of hexane and ethyl acetate (Scheme 5). On treatment of 12a with 10% Pd/C under H2 in the presence of concentrated HCl, pyrazole 2 (4) (a) Brunner, H.; Scheck, T. Chem. Ber. 1992, 125, 701. (b) Luo, Y.; Potvin, P. G. J. Org. Chem. 1994, 59, 1761. (c) Tarrago, G.; Ramdani, A. J. Heterocycl. Chem. 1980, 17, 137. (d) Khan, M. A.; Lynch, B. M. J. Heterocycl. Chem. 1970, 7, 1237. (5) Pyrazoles 5-8 were made from condensation of their corresponding propargylic ketones with hydrazine and used directly without purification. Org. Lett., Vol. 2, No. 20, 2000
Scheme 5
Scheme 7
was obtained in excellent yield. 3-Ethyl-5-isopropylpyrazole 14, the regioisomer of 1, was made from deprotection of the crude mixture 8a/8b, followed by hydrogenation of the isolated major alcohol 13a (Scheme 6).6 This newly devised
Scheme 6
approach can certainly be extended to synthesis of unsymmetrical N-arylpyrazoles bearing alkyl groups at the 3 and 5 positions, considering the good recovery of the intermediates 9a (62% yield), 12a (45% yield), and 13a (56%) without chromatography. These intermediates could be easily converted into a variety of analogous pyrazoles by functionalization of the hydroxy groups. Encouraged by the regioselective arylation of 6, we anticipated a substrate such as 19 with one more methyl substituents on its side chain should have a stronger chelation compared with that of 6. N-Arylation under the same condition would therefore highly favor the regioisomer 20, which is readily converted to 1. It may also be true that the tertiary carbon of pyrazole 19 is sterically hindered enough to effect a high degree of regioselectivity for N1-arylation.3,7,8 Thus, starting from commercially available 2-methyl-3butyn-2-ol (15), THP ether 16 was prepared in 93% yield9 and was treated with n-BuLi at -30 °C followed by amide 17 leading to the propargylic ketone 18 in 61% yield after (6) The structures of all regioisomers were supported by NOE experiments. (7) Elguero, J.; Gonzalez, E.; Jacquier, R. Bull. Soc. Chim. Fr. 1968, 707. (8) 3-tert-Butyl-5-ethylpyrzole (22) was subjected to the same N-arylation with 4-fluoronitrobenzene to give 1-(4-nitrophenyl)-3-tert-butyl-5-ethylpyrzole (23) as a single regioisomer. (9) Chavez, F.; Godinez, R. Synth. Commmun. 1992, 22, 159. (10) To support our rationale, N-arylation of 5 was carried out using KOt-Bu as base in the presence of 1 equiv of 18-crown-6 in refluxing THF. The reaction gave a 1:1 mixture of regioisomers 5a and 5b, in contrast with a 7:1 mixture obtained without 18-crown-6. Org. Lett., Vol. 2, No. 20, 2000
high vacuum distillation (Scheme 7). Condensation of 18 with hydrazine in THF at room temperature yielded pyrazole 19, which was directly subjected to aromatic substitution without purification. Displacement of 4-fluoronitrobenzene with pyrazole 19 in DMSO gave 20 as a single product as anticipated. Subsequent treatment of the resulting crude 20 with a catalytic amount of p-TsOH in aqueous methanol led to pyrazole 21 quantitatively. Pyrazole 21 was then subjected to hydrogenation with 10% Pd/C in acetic acid under 40 psi of H2 for 24 h yielding pyrazole 1, which was purified by recrystallization from a mixture of hexane and ethyl acetate with a recovery of 55% from 18. This facile process involved no chromatography and the intermediates 18 through 21 needed no purification. In conclusion, we have developed a new regioselective approach toward unsymmetrical 3,5-dialkyl-1-arylpyrazoles. On the basis of the observed results in solvents of different polarity (DMSO and THF), it seems likely that association between the substrate and the cation may play the major role in directing the reaction.10 Given the different outcomes in the two solvents, substituent sterics alone cannot be responsible for the observed selectivities and the model in Scheme 2 appears to explain all our currently available data. As a result, an efficient synthesis of 3-isopropyl-5-ethylpyrazole 1 and 3-methyl-5-ethylpyrazole 2 was achieved. Acknowledgment. We wish to thank Dr. John R. Proudfoot for helpful discussions during the course of this work. Note added after ASAP: Due to a processing error, this Letter was posted ASAP on 9/2/00 with incorrect graphics for Schemes 1 and 2. The correct version was posted on 9/7/00. Supporting Information Available: Experimental procedures and spectroscopic data for compounds 1, 2, 3a, 3b, 5, 9a, 9b, 10, 11, 12a, 12b, 13a, 13b, 14, and 17-23. This material is available free of charge via the Internet at http://pubs.acs.org. OL0001822 3109
